There is an ever-increasing interest in herbal or natural-source remedies or medications. Many individuals would rather use such products than conventional pharmaceutical preparations. Additionally, medicinal substances derived from natural products can provide commercial or industrial opportunities for local populations in areas where medicinal plants grow or are cultivated. Moreover, compounds identified as the active ingredients in natural products form an important basis for pharmaceutical research.
Anxiety is a serious disorder that affects many people. Anxiety disorders can be classified into the following sub-categories: generalized anxiety disorder, panic disorders, phobias, obsessive-compulsive disorders, posttraumatic stress disorder, acute stress disorders and anxiety disorders due to medical conditions, substance abuse and not otherwise specified anxiety (American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders, 4th Ed. (DSM-IV). Washington, D.C. (DSM-IV). Anxiety disorders are characterized by three basic components; subjective psychological reports, behavioral responses and physiological responses. A person usually reports subjective feelings of tension, apprehension, dread and expectations of an inability to cope (Alloy, L. B., Jacobson, N. S, & Acocella, J., (1999). Abnormal Psychology: Current Perspectives (pp. 150-172.). McGraw-Hill, Boston Mass.). These feelings can lead the person to behavioral responses as coping mechanisms, such as avoidance of the feared situation, impaired speech and motor functioning, and impaired performance on complex cognitive tasks. Physiological changes are often manifested as well; these include muscle tension, increased heart rate and blood pressure, dry mouth, nausea and dizziness (Gray and McNaughton, 2000; Steimer 2011; Edwards 1991).
Marcgraviaceae is a plant family found in the neotropics.
WO02/091858 to Durst et al. describes the use of Marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives and uses thereof for treating anxiety.
Platanaceae is a family of large monoecious trees that have the characteristic exfoliating bark and is commonly referred to as the “Plane tree Family or Sycamore Family”. As a family, it is represented by a single living genus Platanus containing 6-10 species native to the temperate and sub tropical regions of the Northern Hemisphere.
Stress and anxiety are physiologically distinct phenomena that involve different brain regions, signaling systems, signaling molecules and outcomes. The inhibitory neurotransmitter GABA plays a central role in anxiety. Molecules that target receptors and enzymes in the GABA system are used in the pharmacological treatment of anxiety (Durant et al., 2010; Lydiard, 2003). The prevalence of anxiety disorders is widespread globally and afflicts approximately 12% of the world's population (Davidson 2009; Somers et al. 2006; Tindle et al. 2005). The strategies employed for treating these anxiety disorders are strongly influenced by local socio-economical factors and traditional practices. In more developed areas of the world, the most common approach for treating anxiety is pharmacotherapy (Cloos & Ferreira 2009; Sheehan & Sheehan 2007). More specifically, the most widely prescribed drugs for treating anxiety belong to benzodiazepines which are known to act through the GABArergic system (Dinan 2006; Lader 1984). In more recent decades, busiprone which acts primarily through the serotonergic system is also being used (Dinan 2006). Other pharmacological tools to treat anxiety disorders include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and serotonin-noradrenaline re-uptake inhibitors (SSRI) (Baldwin & Polkinghorn 2005; Sheehan & Sheehan 2007b).
In the vertebrates, the perception of stress initiates a response cascade involving the hypothalamus-pituitary-adrenal (HPA, in mammals) or interrenal (HPI, in fish) axis. The HPA or HPI axis is a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes. When stress is perceived, responses occur in these stress axes, which stimulates the release of corticotrophin-releasing-factor (CRF) from the hypothalamus. This in turn stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH circulates in the blood and stimulates the release of cortisol (corticosterone in rodents) from the adrenal cells (or head kidney cells in fish) into the blood stream. Cortisol is the primary signaling molecule in the HPA axis. Cortisol levels are elevated in animals in response to stress, which leads to physiological changes that can help the animal respond to stress, for example by an enhanced flight or fight response. Cortisol mediates a host of physiological response such as increased catabolism, aggression and down regulation of other functions such as immune responses and reproduction function in mammals. In stress trials, circulating plasma cortisol (corticosterone) is considered a common biomarker to confirm that a stimulus exerts significant stress and to distinguish non-stressed from stressed animals (Gamperl et al., 1994).
These responses are thought to be a short term biological adaptation to stress in animals, however, chronic stress, which can lead to chronically elevated cortisol, hypercortisolism, is maladaptive, and is implicated in disease in both animals and humans. In livestock, elevated stress slows growth and reduces production (Rostagno, 2009). Stress is a concern in aquaculture. The stress response in fish leads to mobilization of energy-rich substrates by depletion of hepatic glycogen stores, elevation of plasma glucose, changes in circulating free fatty acid levels and general inhibition of protein synthesis. These responses have a catabolic effect on fish. Therefore in aquaculture, elevated cortisol adversely affects growth rate, immunity and reproduction (Schreck et al., 2001). In animal production in agriculture, juvenile pigs experience stress when weaned and moved into common pens, elevating cortisol. As a result of their elevated cortisol, they have lower weight gain and their high aggression and lower immune function leads to fights, injuries and more infections. In humans, stress and stress-related illnesses are widespread among people and increasingly a link has been identified between elevated plasma cortisol levels and heart disease, obesity, metabolic syndrome, hyperglycermia (Brown D F et al., 2003). Hypercortisolemia is associated with severe bone loss and depression in hypothalamic Amenorrhea and Anorexia Nervosa (Lawson et al. 2009) and depression (Anagnostis et al., 2009; Carroll et al., 2007; Gathercole and Stewart, 2010; Smith et al., 2005 Parker et al., 2003). In humans, diverse stressful stimuli, including low socioeconomic status, race (Hajat et al., 2010), chronic work stress (Chandola et al., 2006), anxiety and depression (Carroll et al., 2007) stimulate neuroendocrine responses. Pain caused by muscular problems (tension headaches, back and jaw pain, repetitive stress syndrome), gastrointestinal disorders (heart burn, diarrhea, stomach pain) (Anagnostis 2009), mental disorders (eating disorders, anxiety, depression, schizophrenia, insomnia, substance abuse) (Parker, 2003) can also stimulate neuroendocrine responses. Stress related behavior (for example cowering, licking, circling, digging and chewing in dogs) when facing a stressful stimuli such as, transportation, veterinarian visits, vaccination and drug treatments can also result in a neuroendocrine response (Herron, 2008). Animals raised in large scale industrial farms are housed in an environmentally stressful context and express high levels of glucocorticoids, resulting in reduced reproductive efficiency and limited yield in overall productivity.
Notwithstanding the link between hypercortisolism and a variety of human illnesses, pharmacological treatments for hypercortisolism are still under investigation. The hypercortisolism present in Cushing's syndrome is typically caused by a tumor (adrenal or pituitary) and treated with surgery (Sharma and Nieman, 2011). The interest in the role of hypercortisolism in metabolic syndrome stems from the phenotypic similarities between patients with Cushing's and metabolic syndrome. Both include central obesity, impaired glucose tolerance, insulin resistance, type-two diabetes, increased cardiac risk of mortality, osteoporosis and depression (Gathercole and Stewart, 2010). Normalizing cortisol levels usually reverses the symptoms in Cushing's syndrome (Stewart, 2003).
Stress and stress-related illness is widespread, and links between elevated plasma cortisol and heart disease (Smith at al., 2005), obesity (Travison et al., 2007) and depression (Carroll at al., 2007; Parker et al., 2003) have been reported. Aberrations in HPA axis function, including hypercortisolism, are strongly associated with depression (Gallagher at al., 2008). Drugs that inhibit cortisol synthesis, including ketoconazole, aminoglutethimide and metyrapone, have been examined for their therapeutic potential in treating depression (Kling et al., 2009; Starkman et al., 2001) and have shown some promise in bipolar patients with depressive symptoms (ketoconazole) (Brown et al., 2001), and patients with major depressive disorder (MDD). In a blind, placebo-controlled study with patients suffering from MDD, co-delivery of metyrapone (an inhibitor of cortisol synthesis by blocking the mitochrondrial steroidogenic enzyme steroid 11-β hydroxylase) and a standard serotonergic antidepressant (nefazodone or fluvoxamine), significantly reduced depression (50% reduction in HAM-D scores at day 35 of treatment) (Jahn et al., 2004). However, despite the potential of cortisol-lowering drugs to treat depression, they are also associated with serious side-effects (Thomson and Craighead, 2008), including ketoconazole's potential for liver toxicity (Kim et al., 2003) and strong inhibition of cytochrome P450 3A (Cook et al., 2004), with the consequence that in some clinical trials up to 20% of patients drop out due to the side-effects (Wolkowitz et al., 1999).
In the context of metabolic syndrome, inhibition of the enzyme 11β hydroxysteroid dehydrogenase 1 (11-β HSD1) to treat hypercortisolism has been examined (Gathercole and Stewart, 2010). At the pre-receptor level, 11-β HSD1 converts metabolically inactive cortisone to active cortisol (11-dehydrocorticosterone to corticosterone in rodents). In rodent models of metabolic syndrome, inhibition of 11-β HSD1 improves metabolic profile (Gathercole and Stewart, 2010). A recent Phase I clinical trial with a selective 11-β HSD1 inhibitor shows good tolerability and no activation of the HPA axis in healthy patients (Courtney et al., 2008).
Post Traumatic Stress Disorder (PTSD) is an anxiety disorder that results from exposure to a traumatic event. The disabling psychological symptoms associated with PTSD can occur long after the exposure to the traumatic event(s). The DSM-V encompasses several symptoms related to the disorder, including numbing, avoidance, increased arousal and it is often associated re-experiencing of the past trauma. PTSD symptoms elicit severe distress and/or impair normal functioning. PTSD has become a global health issue, with prevalence rates ranging from 1.3% to 37.4%. As PTSD is often accompanied with other health conditions, it is difficult to appropriately pinpoint a specific treatment regimen for each individual of them. Serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors (SNRIs) and benzodiazepines, are typically used to treat PTSD. However, the outcomes are variable, as majority of affected individuals do not experience full remission. Furthermore, there are a number of side effects (e.g. sedation, decreased libido, weight gain) with these drugs. The usage of anxiolytic plants for treating the symptoms associated with PTSD has been suggested by Maddox et al. (2013), Passie et al. (2012) and Sarris et al. (2013).
Conditioned fear is relevant to Post Traumatic Stress Disorder. Pavlovian fear conditioning (FC) is an important paradigm for studying memory processes and related brain circuits that are relevant to PTSD (Cain et al., 2012; Parson et al. 2013). Models of FC in rodents include conditioned emotional response (CER) and fear potentiated startle paradigm (FPS). FC occurs when a neutral stimulus (e.g. light or tone) is conditioned (CS) or temporally paired with naturally aversive unconditioned stimuli (US; foot shock). Typically, after a number of repeated pairings, the CS itself acquires the capacity to elicit responses akin to that of US, that is a fear response. Thus, FC is an extremely powerful form of associative learning; if the CS is sufficiently salient and the US sufficiently aversive, even a single brief episode can lead to strong fear memories that can last a lifetime. FC studies have greatly enhanced our understanding of the neurobiology of memory and emotional responding. Although FC does not necessarily produce PTSD, psychological and neural processes mediating FC likely engage brain circuits and processes that contribute to PTSD. FC has several important features and phases that may make distinct contributions to PTSD or treatment (Cain et al., 2012; Parson et al. 2013).
Acquisition refers to the process by which the organism learns that the conditioned stimulus predicts the unconditioned stimulus. Treatments that block the acquisition of fear conditioning are applied before CS-US pairings and prevent the development of short-term memory (STM) memory, tested within a few hours, and consequently the formation of long-term memory (LTM), tested many hours or days later.
The consolidation of fear conditioning refers to the transformation of the short-term memory from a labile state immediately after acquisition to a more permanent state with the passage of time. Treatments that disrupt the consolidation of memory are usually applied a few minutes to a few hours after CS-US pairings, leaving STM intact but resulting in LTM disruption.
Retrieval (also refers to as expression) refers to the conditioned responding that occurs after CS-US relationship has been established. Retrieval is assessed by presenting the CS alone and then measuring the conditioned response. Treatments that disrupt retrieval are typically administered shortly before the conditioned response is assessed. Drugs that disrupt retrieval may blunt PTSD symptoms.
PTSD research has been focused on two other phases on CF, namely reconsolidation and extinction. Reconsolidation occurs after retrieval. During a brief window of time after the retrieval of the fearful memories, the specific memory and its association with an emotional response, return to an unstable state, during which time the “repackaging” of the memory is vulnerable to pharmacological intervention. Reconsolidation of memory is considered to be disrupted when a drug is applied shortly after retrieval and leaves STM intact yet disrupts LTM.